Microvessel quantitation in invasive breast cancer by staining for factor VIII-related antigen

Ogawa, Yoshinari; Chung, Yong‐Suk; Nakata, Bunzo; Takatsuka, Satoshi; Maeda, Kotaro; Sawada, Terumasa; Kato, Yasushi; Yoshikawa, Kohei; Sakurai, Minako; Sowa, Michio

doi:10.1038/bjc.1995.251

Cited by 84 publications

(35 citation statements)

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“…Several studies, including nearly 4000 patients, have evaluated intratumoural vessel profiles as a prognostic variable in breast cancer (Bosari et al, 1992;Hall et al, 1992;Horak et al, 1992;Weidner et al, 1992;Khanuja et al, 1993;Toi et al, 1993Toi et al, , 1995Van Hoef et al, 1993;Fox et al, 1994Fox et al, , 1995bFregene et al, 1994;Gasparini et al, 1994Gasparini et al, , 1995Lipponen et al, 1994;Obermair et al, 1994Obermair et al, , 1995Axelsson et al, 1995;Barbareschi et al, 1995;Bevilacqua et al, 1995;Costello et al, 1995;Goulding et al, 1995;Ogawa et al, 1995;Heimann et al, 1996;Kohlberger et al, 1996;Leek et al, 1996;Morphopoulos et al, 1996;Simpson et al, 1996;Charpin et al, 1997;Karelia et al, 1997;Martin et al, 1997;Acenero et al, 1998). However, these studies have reported contradictory results, without reliable evidence allowing for the clinical use of angiogenesis as a prognostic factor in breast cancer.…”

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confidence: 99%

Vascular grading of angiogenesis: prognostic significance in breast cancer

et al. 2000

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SummaryThe study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11 years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers was moderately reproduced (κ = 0.59). Vascular grade was significantly associated with axillary node involvement, tumour size, malignancy grade, oestrogen receptor status and histological type. In univariate analyses vascular grade significantly predicted recurrence free survival and overall survival for all patients (P < 0.0001), node-negative patients (P < 0.0001) and node-positive patients (P < 0.0001). Cox multivariate regression analysis showed that vascular grading contributed with independent prognostic value in all patients (P < 0.0001). A prognostic index including the vascular grade had clinical impact for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer.

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confidence: 99%

Vascular grading of angiogenesis: prognostic significance in breast cancer

et al. 2000

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“…Recently it has been suggested that the intensity of angiogenesis, as measured by the intratumoral microvessel density, may be inversely correlated with time of survival of patients with invasive breast cancer (Bosari et al, 1992;Horak et al, 1992;Weidner et al, 1992;Toi et al, 1993;Gasparini et al, 1994;Obermair et al, 1994;Bevilacqua et al, 1995, Fox et al, 1995Ogawa et al, 1995;), although not all studies have found this association (Hall et al, 1992;Van Hoef et al, 1993;Axelsson et al, 1995;Goulding et al, 1995;Costello et al, 1995). This may be the result of the different methodologies used both to stain and to count the microvessels in the tumour.…”

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confidence: 99%

“…Early studies only assessed one x 200 microscopic field for microvessel density and this figure was used for statistical analysis. In subsequent studies, the number of 'hotspots' counted for each tumour section has varied from 1 to 5 and the density of microvessels per field has been recorded either as the highest count (Weidner et al, 1991;Horak et al, 1992;Gasparini et al, 1994) or as the mean of three, four or five fields (Bosari et al, 1992;Hall et al, 1992;Toi et al, 1993;Van Hoef et al, 1993;Miliaras et al, 1995;Ogawa et al, 1995). Only the maximum number of microvessels is recorded because the intratumoral vessel density is heterogeneous and it is thought that blood vessel invasion and hence systemic dissemination of tumour cells is more likely to occur in the areas of highest vessel density (Horak et al, 1992).…”

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Examining the technique of angiogenesis assessment in invasive breast cancer

Martín

Green²,

Renshaw³

et al. 1997

Br J Cancer

108

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Summary The intensity of angiogenesis as measured by the density of microvessels has been reported to be associated with a poor prognosis in invasive breast cancer in some, but not all, studies. The reasons for these discrepancies may be variations in the methodologies used. The monoclonal antibody used to identify the microvessels, the number of high-density areas or 'hotspots' counted and the type of value taken for statistical analysis (highest count or mean count) have varied between the different studies. We have assessed which of the three commonly used monoclonal antibodies provides the best visualization of microvessels in invasive breast cancer and have used methods that give reproducible data for the optimum number of 'hotspots' to count for each reagent. Thus, microvessels in formalin-fixed paraffin-embedded specimens from 174 primary breast cancers were immunohistochemically stained with monoclonal antibodies to FVIIIRAg, CD31 and CD34 and ten fields counted at 200 x magnification for each antibody. The highest count and the mean value of the highest of three, five and ten counts were used to examine the relationship between the density of microvessels and overall survival of patients with a median follow-up time of 7.1 years. Antibodies to CD31 and CD34 identified more vessels than antibodies to FVIIIRAg (median highest count per mm2: CD31 = 100, CD34 = 100, FVIIIRAg = 81). The monoclonal antibody to CD31, however, was the least reliable antibody, immunohistochemically staining only 87% of sections compared with 98% for the monoclonal to CD34 and 99% for the monoclonal to FVIIIRAg. There was a high degree of correlation between the number of vessels stained by the different antibodies, though there were some considerable differences in actual counts for serial sections of the same specimen stained by the different antibodies. Patients could be divided into two groups corresponding to those with high microvessel densities and those with low microvessel densities. Using Kaplan-Meier survival curves, there was a close association for all three antibodies between vessel density and survival whichever method of recording the highest vessel densities was used. Using log-rank tests and Cox's regression analysis, anti-CD34 gave the most significant results of the three antibodies, whereas a simple cut-off at the 75th percentile for the high and low groups produced the best association with patient survival. For anti-CD34 the highest microvessel density (P = 0.0014) and the mean value of the highest three microvessel densities (P= 0.004) showed a good correlation with patient death, whereas for anti-CD31 (P= 0.008) and anti-FVIIIRAg (P= 0.007) the highest count gave the best correlation using Cox's regression analysis.

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“…21 We used rabbit polyclonal antibody against factor VIII-related antigen (Dako Japan Co., Kyoto, Japan) and an ABC kit (Nichirei Co., Tokyo, Japan). The polyclonal antibody was diluted 1:200 and reacted with tissue specimens at 4°C overnight.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI-166, on experimental pancreatic cancer

et al. 2001

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The antitumor effect of a new matrix metalloproteinase inhibitor, MMI-166, which is a selective inhibitor of MMP-2 and -9, was examined in the hamster pancreatic cancer cell line PGHAM-1. In vitro, MMI-166 inhibited the gelatinase activity of MMP-2 and -9 derived from PGHAM-1 cells, and dose-dependently inhibited invasion of PGHAM-1 through a basement membrane-like barrier. MMI-166 showed no apparent cytotoxicity to PGHAM-1 cells in culture at 100 g/ml. MMI-166 (200 mg/kg) or vehicle were administered orally, once daily, from day 1 until day 21 after implantation in the orthotopic implantation model of PGHAM-1. MMI-166 significantly reduced the incidence of liver surface metastasis from 66.7% to 20.0%, and it reduced the number of liver surface metastases per animal from 6.17 to 2.00, but this reduction was not significant. Key words: selective MMP inhibitor; pancreatic cancer; antitumor effectPancreatic cancer is characterized by extensive local invasion of adjacent structures, perineural invasion, early metastasis to liver and lymph nodes and a poor prognosis. 1,2 The ability of tumor cells to degrade adjacent extracellular matrix is considered an essential step in the processes of invasion and metastasis. 3,4 Matrix metalloproteinases (MMPs) are a family of structurally related zymogens capable of degrading extracellular matrix, including basement membrane. They are secreted by cancer cells and adjacent stromal cells in latent form and then converted into their active form. MMPs are crucial for tumor cell migration through the basement membrane and extracellular matrix, and for tumor cell intravasation and extravasation. 3,5 MMP-2-degrading type IV collagen, which is a main component of basement membranes, is expressed in pancreatic cancer 6 and plays an important role in invasion and metastasis. 7,8 MMPs also appear to be involved in angiogenesis, by mediating tissue remodeling and penetration of the extracellular matrix by activated endothelial cells. 4 Angiogenesis, which is essential for tumor growth and metastasis, is one of the important steps in the transition of tumors from small, harmless clusters of mutated cells to large, malignant growths, capable of spreading to other organs throughout the body. 9 When angiogenesis is blocked, tumor growth is suppressed, and tumor cell proliferation is balanced by apoptosis. 10 MMP-2 plays an especially important role in angiogenesis and tumor progression in some cancers. 11 Hamster pancreatic cancer cell line PGHAM-1 was derived from BOP (N-nitrosobis(2-oxopropyl)amine)-induced hamster pancreatic cancer cells as a result of repeated passage by subcutaneous implantation. It is a ductal adenocarcinoma that closely resembles human pancreatic carcinoma, and it often gives rise to liver metastasis shortly after implantation into the pancreas. [12][13][14] The PGHAM-1 cell line is useful for studying pancreatic cancer and liver metastasis by pancreatic cancer.Many studies have been conducted on the inhibitory effect of MMP inhibitors on invasion and metastasis in var...

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Microvessel quantitation in invasive breast cancer by staining for factor VIII-related antigen

Cited by 84 publications

References 23 publications

Vascular grading of angiogenesis: prognostic significance in breast cancer

Vascular grading of angiogenesis: prognostic significance in breast cancer

Examining the technique of angiogenesis assessment in invasive breast cancer

Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI-166, on experimental pancreatic cancer

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